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Long-Lived Mice Lacking p66shc

As some try to build a better mousetrap, others try to make mice that live longer. The latest advance in the latter category emerges from studies of a signaling protein, p66shc. Although related to p52shc and p46shc proteins that couple receptor tyrosine kinases to activation of Ras, the p66 splice variant seems to signal in a different way. It is phosphorylated on serine residues in response to oxidative stress. Thus it is thought to function in regulation of the response to oxidative damage. What is surprising, though, is that mice that lack p66shc live almost one-third longer than their counterparts that produce the protein. It is not exactly known how this works, but one favored hypothesis is that the p66shc pathway promotes apoptosis in cells that have suffered oxidative damage. Although this strategy may be useful during development, in the aging adult such a pathway might be hazardous to the health.